Omega-3 supplements did not reduce fractures during a median 5.3-year follow-up in the more than 25,000 generally healthy men and women (≥ age 50 and ≥ age 55, respectively) in the Vitamin D and Omega-3 Trial (VITAL).
The large randomized controlled trial tested whether omega-3 fatty acid or vitamin D supplements prevented cardiovascular disease or cancer in a representative sample of midlife and older adults from 50 US states — which they did not. In a further analysis of VITAL, vitamin D supplements (cholecalciferol, 2000 IU/day) did not lower the risk of incident total, nonvertebral, and hip fractures compared with placebo.
Now this new analysis shows that omega-3 fatty acid supplements (1g/day of fish oil) did not reduce the risk of such fractures in the VITAL population either. Meryl S. LeBoff, MD, presented the latest findings during an oral session at the American Society of Bone and Mineral Research (ASBMR) 2022 Annual Meeting.
“In this, the largest randomized controlled trial in the world, we did not find an effect of omega-3 fatty acid supplements on fractures,” LeBoff, from Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.
The current analysis did “unexpectedly” show that among participants who received the omega-3 fatty acid supplements, there was an increase in fractures in men, and fracture risk was higher in people with a normal or low body mass index (BMI) and lower in people with higher BMI.
However, these subgroup findings need to be interpreted with caution and may be due to chance, LeBoff warned. The researchers will be investigating these findings in further analyses.
Should Patients Take Omega-3 Supplements or Not?
Asked whether, in the meantime, patients should start or keep taking fish oil supplements for possible health benefits, she noted that certain individuals might benefit.
For example, in VITAL, participants who ate less than 1.5 servings of fish per week and received omega-3 fatty acid supplements had a decrease in the combined cardiovascular endpoint, and Black participants who took fish oil supplements had a substantially reduced risk of the outcome, regardless of fish intake.
“I think everybody needs to review [the study findings] with clinicians and make a decision in terms of what would be best for them,” she said.
Session co-moderator Bente Langdahl, MD, PhD, commented to Medscape Medical News that “many people take omega-3 because they think it will help” knee, hip, or other joint pain.
Perhaps men are more prone to joint pain due to osteoarthritis and the supplements lessen the pain, so these men became more physically active and more prone to fractures, she speculated.
The current study tells us that, “so far, we haven’t been able to demonstrate a reduced rate of fractures with fish oil supplements in clinical randomized trials” conducted in relatively healthy and not the oldest patients, she summarized. “We’re not talking about 80-year-olds,” she noted.
In this “well-conducted study, they were not able to see any difference” with omega-3 fatty acid supplements versus placebo, but apparently, there are no harms associated with taking these supplements, she said.
To patients who ask her about such supplements, Langdahl advises: “Try it out for 3 months. If it really helps you, if it takes away your joint pain or whatever, then that might work for you. But then remember to stop again because it might just be a temporary effect.”
Could Fish Oil Supplements Protect Against Fractures?
An estimated 22% of US adults aged 60 and older take omega-3 fatty acid supplements, LeBoff noted.
Preclinical studies have shown that omega-3 fatty acids reduce bone resorption and have anti-inflammatory effects, but observational studies have reported conflicting findings.
The researchers conducted this ancillary study of VITAL to fill these knowledge gaps.
VITAL enrolled a national sample of 25,871 US men and women, including 5106 Black participants, with a mean age of 67 and a mean BMI of 28 kg/m2.
Importantly, participants were not recruited by low bone density, fractures, or vitamin D deficiency. Prior to entry, participants were required to stop taking omega-3 supplements and limit non-study vitamin D and calcium supplements.
The omega-3 fatty acid supplements used in the study contained eicosapentaenoic acid and docosahexaenoic acid in a 1.2:1 ratio.
VITAL had a 2×2 factorial design whereby 6463 participants were randomized to receive the omega-3 fatty acid supplement and 6474 were randomized to placebo. (Remaining participants were randomized to receive vitamin D or placebo.)
Participants in the omega-3 fatty acid and placebo groups had similar baseline characteristics. For example, about half (50.5%) were women, and on average, they ate 1.1 servings of dark-meat fish (such as salmon) per week.
Participants completed detailed questionnaires at baseline and each year.
Plasma omega-3 levels were measured at baseline and, in 1583 participants, at 1 year of follow-up. The mean omega-3 index rose 54.7% in the omega-3 fatty acid group and changed < 2% in the placebo group at 1 year.
Study pill adherence was 87.0% at 2 years and 85.7% at 5 years.
Fractures were self-reported on annual questionnaires and centrally adjudicated in medical record review.
No Clinically Meaningful Effect of Omega-3 Fatty Acids on Fractures
During a median 5.3-year follow-up, researchers adjudicated 2133 total fractures and confirmed 1991 fractures (93%) in 1551 participants.
Incidences of total, nonvertebral, and hip fractures were similar in both groups.
Compared with placebo, omega-3 fatty acid supplements had no significant effect on risk of total fractures (HR, 1.02; 95% CI, 0.92 – 1.13), nonvertebral fractures (HR, 1.01; 95% CI, 0.91 – 1.12), or hip fractures (HR, 0.89; 95% CI, 0.61 – 1.30), all adjusted for age, sex, and race.
The “confidence intervals were narrow, likely excluding a clinically meaningful effect,” LeBoff noted.
Among men, those who received fish oil supplements had a greater risk of fracture than those who received placebo (HR, 1.27; 95% CI, 1.07 – 1.51), but this result “was not corrected for multiple hypothesis testing,” LeBoff cautioned.
In the overall population, participants with a BMI < 25 kg/m2 who received fish oil versus placebo had an increased risk of fracture, and those with a BMI ≥ 30 kg/m2 who received fish oil versus placebo had a decreased risk of fracture, but the limits of the confidence intervals crossed 1.00.
After excluding digit, skull, and pathologic fractures, there was no significant reduction in total fractures (HR, 1.02; 95% CI, 0.92 – 1.14), nonvertebral fractures (HR, 1.02; 95% CI, 0.92 – 1.14), or hip fractures (HR, 0.90; 95% CI, 0.61 – 1.33), with omega-3 supplements versus placebo.
Similarly, there was no significant reduction in risk of major osteoporotic fractures (hip, wrist, humerus, and clinical spine fractures) or wrist fractures with omega-3 supplements versus placebo.
VITAL only studied one dose of omega-3 fatty acid supplements, and results may not be generalizable to younger adults, or older adults living in residential communities, LeBoff noted.
The study was supported by grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases. VITAL was funded by the National Cancer Institute and the National Heart, Lung, and Blood Institute. LeBoff and Langdahl have reported no relevant financial relationships.
ASBMR 2022. Presented September 11, 2022. Abstract 1051.
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